Plus sur les nanotubes.

Researchers at Rice University and the University of Texas MD Anderson Cancer Center have refined and, for the first time, run in vivo tests of a method that may allow nanotube-based probes to locate specific tumors in the body. Their ability to pinpoint tumors with submillimeter accuracy could eventually improve early detection and treatment of ovarian cancer.

The noninvasive technique relies on single-walled carbon nanotubes that can be optically triggered to emit shortwave infrared light. The Rice lab of chemist Bruce Weisman, a pioneer in the discovery and interpretation of the phenomenon, reported the new results in the American Chemical Society journal ACS Applied Materials and Interfaces.

For this study, the researchers used the technique to pinpoint small concentrations of nanotubes inside rodents. The lab of co-author Dr. Robert Bast Jr., an expert in ovarian cancer and vice president for translational research at MD Anderson, inserted gel-bound carbon nanotubes into the ovaries of rodents to mimic the accumulations that are expected for nanotubes linked to special antibodies that recognize tumor cells. The rodents were then scanned with the Rice lab's custom-built optical device to detect the faint emission signatures of as little as 100 picograms of nanotubes.

The device irradiated the rodents with intense red light from an array of light-emitting diodes and read fluorescent signals with a specialized sensitive detector. Because different types of tissue absorb emissions from the nanotubes differently, the scanner took readings from many locations to triangulate the tumor's exact location, as confirmed by later MRI scans.

Weisman said it should be possible to noninvasively find small ovarian tumors within rodents used for medical research by linking nanotubes to antibody biomarkers and administering the biomarkers intravenously. The biomarkers would accumulate at the tumor site. He said more refined versions of the optical scanner may then be able to locate a tumor within seconds, and further advances may extend the method's application to human cancer detection. The new results suggested that antibody-nanotube probes could potentially detect tumors with as few as 100 ovarian cancer cells, which could make it a valuable tool for early detection.

Scientists have shown that gold nanotubes have many applications in fighting cancer: internal nanoprobes for high-resolution imaging; drug delivery vehicles; and agents for destroying cancer cells.

The study, published today in the journal Advanced Functional Materials, details the first successful demonstration of the biomedical use of gold nanotubes in a mouse model of human cancer.

Study lead author Dr Sunjie Ye, who is based in both the School of Physics and Astronomy and the Leeds Institute for Biomedical and Clinical Sciences at the University of Leeds, said: "High recurrence rates of tumours after surgical removal remain a formidable challenge in cancer therapy. Chemo- or radiotherapy is often given following surgery to prevent this, but these treatments cause serious side effects.

Gold nanotubes -- that is, gold nanoparticles with tubular structures that resemble tiny drinking straws -- have the potential to enhance the efficacy of these conventional treatments by integrating diagnosis and therapy in one single system."

The researchers say that a new technique to control the length of nanotubes underpins the research. By controlling the length, the researchers were able to produce gold nanotubes with the right dimensions to absorb a type of light called 'near infrared'.

The study's corresponding author Professor Steve Evans, from the School of Physics and Astronomy at the University of Leeds, said: "Human tissue is transparent for certain frequencies of light -- in the red/infrared region. This is why parts of your hand appear red when a torch is shone through it.

"When the gold nanotubes travel through the body, if light of the right frequency is shone on them they absorb the light. This light energy is converted to heat, rather like the warmth generated by the Sun on skin. Using a pulsed laser beam, we were able to rapidly raise the temperature in the vicinity of the nanotubes so that it was high enough to destroy cancer cells."

In cell-based studies, by adjusting the brightness of the laser pulse, the researchers say they were able to control whether the gold nanotubes were in cancer-destruction mode, or ready to image tumours.

In order to see the gold nanotubes in the body, the researchers used a new type of imaging technique called 'multispectral optoacoustic tomography' (MSOT) to detect the gold nanotubes in mice, in which gold nanotubes had been injected intravenously. It is the first biomedical application of gold nanotubes within a living organism. It was also shown that gold nanotubes were excreted from the body and therefore are unlikely to cause problems in terms of toxicity, an important consideration when developing nanoparticles for clinical use.

Study co-author Dr James McLaughlan, from the School of Electronic & Electrical Engineering at the University of Leeds, said: "This is the first demonstration of the production, and use for imaging and cancer therapy, of gold nanotubes that strongly absorb light within the 'optical window' of biological tissue.

"The nanotubes can be tumour-targeted and have a central 'hollow' core that can be loaded with a therapeutic payload. This combination of targeting and localised release of a therapeutic agent could, in this age of personalised medicine, be used to identify and treat cancer with minimal toxicity to patients."

The use of gold nanotubes in imaging and other biomedical applications is currently progressing through trial stages towards early clinical studies.

(Aug. 5, 2009) — By injecting man-made, microscopic tubes into tumors and heating them with a quick, 30-second zap of a laser, scientists have discovered a way to effectively kill kidney tumors in nearly 80 percent of mice. Researchers say that the finding suggests a potential future cancer treatment for humans.

The study appears in the August issue of PNAS (Proceedings of the National Academy of Sciences). It is the result of a collaborative effort between Wake Forest University School of Medicine, the Wake Forest University Center for Nanotechnology and Molecular Materials, Rice University and Virginia Tech.

L'étude est apparue en aoüt dans le numéro de PNAS.

"When dealing with cancer, survival is the endpoint that you are searching for," said Suzy Torti, Ph.D., lead investigator for the study and professor of biochemistry at Wake Forest University School of Medicine. "It's great if you can get the tumor to shrink, but the gold standard is to make the tumor shrink or disappear and not come back. It appears that we've found a way to do that."

Nanotubes are long, thin, sub-microscopic tubes made of carbon. For the study, researchers used multi-walled nanotubes (MWCNTs), which contain several nanotubes nested within each other, prepared for the study by the Center for Nanotechnology and Molecular Materials. The tubes, when non-invasively exposed to laser-generated near-infrared radiation, respond by vibrating, creating heat. If enough heat is conducted, tumor cells near the tubes begin to shrink and die.

Using a mouse model, researchers injected kidney tumors with different quantities of MWCNTs and exposed the area to a three-watt laser for 30 seconds.

Researchers found that the mice who received no treatment for their tumors died about 30 days into the study. Mice who received the nanotubes alone or laser treatment alone survived for a similar length of time. However, in the mice who received the MWCNTs followed by a 30-second laser treatment, researchers found that the higher the quantity of nanotubes injected, the longer the mice lived and the less tumor regrowth was seen. In fact, in the group that received the highest dose of MWCNTs, tumors completely disappeared in 80 percent of the mice. Many of those mice continued to live tumor-free through the completion of the study, which was about nine months later.

"You can actually watch the tumors shrinking until, one day, they are gone," Torti said. "Not only did the mice survive, but they maintained their weight, didn't have any noticeable behavioral abnormalities and experienced no obvious problems with internal tissues. As far as we can tell, other than a transient burn on the skin that didn't seem to affect the animals and eventually went away, there were no real downsides – that's very encouraging."

Current thermal ablation, or heat therapy, treatments for human tumors include radiofrequency ablation, which applies a single-point source of heat to the tumor rather than evenly heating the tumor throughout, like the MWCNTs were able to. In addition to the MWCNTs used in this study, other nanomaterials, such as single-walled carbon nanotubes and gold nanoshells, are also currently undergoing experimental investigation as cancer therapies at other institutions.

"MWCNTs are more effective at producing heat than other investigational nanomaterials," Torti said. "Because this is a heat therapy rather than a biological therapy, the treatment works on all tumor types if you get them hot enough. We are hopeful that we will be able to translate this into humans."

Before the treatment can be tested in humans, however, studies need to be done to test the toxicity and safety, looking to see if the treatment causes any changes to organs over time, as well as the pharmacology of the treatment, looking at things such as what happens to the nanotubes, which are synthetic materials, over time.

The treatment would need to be tested in larger animals before being tested in human trials, as well. Conceptually, however, Torti said there is no barrier to applying the therapy into humans to treat tumors close to the surface of the skin, such as in the oral cavity and bladder wall.

Biomedical scientists at UT Southwestern Medical Center and nanotechnology experts from UT Dallas describe their experiments in a study available online and in an upcoming print issue of Proceedings of the National Academy of Sciences.

Scientists are able to use biological molecules called monoclonal antibodies that bind to cancer cells. Monoclonal antibodies can work alone or can be attached to powerful anti-cancer drugs, radionuclides or toxins to deliver a deadly payload to cancer cells.

In this study, the researchers used monoclonal antibodies that targeted specific sites on lymphoma cells to coat tiny structures called carbon nanotubes. Carbon nanotubes are very small cylinders of graphite carbon that heat up when exposed to near-infrared light. This type of light, invisible to the human eye, is used in TV remote controls to switch channels and is detected by night-vision goggles. Near-infrared light can penetrate human tissue up to about 1½ inches.

In cultures of cancerous lymphoma cells, the antibody-coated nanotubes attached to the cells' surfaces. When the targeted cells were then exposed to near-infrared light, the nanotubes heated up, generating enough heat to essentially "cook" the cells and kill them. Nanotubes coated with an unrelated antibody neither bound to nor killed the tumor cells.

"Using near-infrared light for the induction of hyperthermia is particularly attractive because living tissues do not strongly absorb radiation in this range," said Dr. Ellen Vitetta, director of the Cancer Immunobiology Center at UT Southwestern and senior author of the study. "Once the carbon nanotubes have bound to the tumor cells, an external source of near-infrared light can be used to safely penetrate normal tissues and kill the tumor cells.

"Demonstrating this specific killing was the objective of this study. We have worked with targeted therapies for many years, and even when this degree of specificity can be demonstrated in a laboratory dish, there are many hurdles to translating these new therapies into clinical studies. We're just beginning to test this in mice, and although there is no guarantee it will work, we are optimistic."

The use of carbon nanotubes to destroy cancer cells with heat is being explored by several research groups, but the new study is the first to show that both the antibody and the carbon nanotubes retained their physical properties and their functional abilities -- binding to and killing only the targeted cells. This was true even when the antibody-nanotube complex was placed in a setting designed to mimic conditions inside the human body.

Biomedical applications of nanoparticles are increasingly attracting the attention of basic and clinical scientists. There are, however, challenges to successfully developing nanomedical reagents. One is the potential that a new nanomaterial may damage healthy cells and organisms. This requires that the effects of nanomedical reagents on cells and organisms be thoroughly studied to determine whether the reagents are inherently toxic.

"There are rational approaches to detecting and minimizing the potential for nonspecific toxicity of the nanoparticles developed in our studies," said Dr. Rockford Draper, leader of the team from UT Dallas and a professor of molecular and cell biology.

Other researchers from UT Southwestern involved in the research were lead authors Pavitra Chakravarty, a graduate student in biomedical engineering, and Dr. Radu Marches, assistant professor in the Cancer Immunobiology Center. Authors from UT Dallas' Alan G. MacDiarmid NanoTech Institute were Dr. Inga Musselman, Dr. Paul Pantano and graduate student Pooja Bajaj. Two undergraduate students in UT Southwestern's Summer Undergraduate Research Fellowship program -- Austin Swafford from UT Dallas and Neil Zimmerman from the Massachusetts Institute of Technology -- also participated.

The research was supported by the Cancer Immunobiology Center at UT Southwestern, the Robert A. Welch Foundation, the Department of Defense and the Center for Applied Biology at UT Dallas.

Dr. Vitetta is a co-inventor on a patent describing the techniques outlined in the study.

(Jan. 29, 2008) — Carbon nanotubes-cylinders so tiny that it takes 50,000 lying side by side to equal the width of a human hair-are packed with the potential to be highly accurate vehicles for administering medicines and other therapeutic agents to patients. But a dearth of data about what happens to the tubes after they discharge their medical payloads has been a major stumbling block to progress.

Now, Stanford researchers, who spent months tracking the tiny tubes inside mice, have found some answers.

Studies in mice already had shown that most nanomaterials tend to accumulate in organs such as the liver and spleen, which was a concern because no one knew how long they could linger. But fears that the tiny tubes might be piling up in vital organs, like discarded refrigerators at the bottom of a rural ravine, can now be put to rest, said Hongjie Dai, the J. G. Jackson and C. J. Wood Professor of Chemistry at Stanford, whose research team has demonstrated that the nanotubes exit the organs.

Dai and his group found that the carbon nanotubes leave the body primarily through the feces, with some by way of the urine. ''That's nice to know,'' Dai said. ''This now proves that they do get out of the system.''The full extent of the news, which is scheduled to be published the week of Jan. 28 in Proceedings of the National Academy of Sciences Online Early Edition (PNAS), is even better than that: The three-month-long study also allays worries that the nanotubes, by simply remaining in the organs for a long time, would prove toxic to the mouse.

''None of the mice died or showed any anomaly in the blood chemistry or in the main organs,'' said Dai, senior author on the PNAS paper. ''They appear very healthy, and they are gaining weight, just like normal mice. There's no obvious toxicity observed.'' The lack of toxicity of nanotubes in mice is consistent with a previous pilot study done by Sanjiv Gambhir, a professor of radiology at Stanford, and his research group in collaboration with Dai's group.

''This is the first time anyone has done a systematic circulation and excretion study like this for nanotubes, and data on other nano particles is also scarce,'' Dai said. ''The excretion pathway may apply to other nano materials and may need to be looked at closely like this also.''Previous research published by Dai's group has demonstrated the potential for using nanotubes in treating cancerous cells and targeting tumors in mice.

His group used Raman spectroscopy, a method of applying light from a laser beam that effectively ''illuminates'' the presence of the target molecules in the organs of the mice.

Being hit with light from the beam causes a detectable change in the state of a molecule's energy. Carbon nanotubes, composed entirely of carbon atoms that are mostly arranged in linked hexagonal rings, give off a strong signal in response to the beam. This allowed the researchers to pinpoint the position of the chosen molecules, as well as ascertain their abundance in the blood or organs.

Previous detection methods that relied on attaching fluorescent labels or spectroscopic tags to the nanotubes had yielded unreliable results. The attachments tended to either come loose from the tubes or decay over time spans ranging from a few days to only a few hours-far too short to reveal the ultimate fate of the nanotubes.

While knowing the carbon nanotubes will move through the digestive system at a healthy pace is critical to future practical applications, it is also crucial that the nanotubes not enter the digestive system too soon after being injected; they need to spend enough time in the circulatory system to find their way to their target location.

The key to fine-tuning the carbon nanotubes' speed of circulation turns on how the basic, bare-bones floor model is chemically accessorized.''You can make the nanotubes circulate a very long time in the blood, if the chemistry is done right,'' Dai said. The researchers found that coating their carbon nanotubes with polyethylene glycol (PEG), a common ingredient in cosmetics, worked best.

They used a form of PEG with three little limbs sprouting off a central trunk. ''Those provide better shielding to the nanotube than just a single branch. Therefore, they interact less with the biological molecules around them,'' Dai said.

The team stuffed the PEG liberally into the linked hexagonal rings that compose the nanotubes, prompting Dai to describe the end result as resembling rolled-up chicken wire with feathers sticking out all over.Though they may sound less than gorgeous visually, the feathery nanotubes turned in a beautiful performance in practical terms, Dai said. The coating of PEG made the nanotubes highly water soluble, which helped them to stay in the blood instead of being absorbed.

''They circulate in the blood for about 10 hours or so in mice, which seems to be a good length of time,'' Dai said.

The right chemical coating on nanotubes also can help ease them out of the mouse in a timely fashion, and the three-branched PEG was effective there, too.

Dai's earlier research demonstrated that nanotubes have promise for treating cancer with two different approaches. Once they have zeroed in on the target cells, shining light on the nanotubes causes them to generate heat, which can kill cancer cells. The other method is to rig the nanotubes to accumulate at targeted sites, where they can deliver medication from within the tubes.